First, we compared biomarkers of endothelial dysfunction vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [E
Trang 1Open Access
R634
Vol 7 No 3
Research article
Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis
Patrick H Dessein1, Barry I Joffe2 and Sham Singh3
1 Department of Rheumatology, Johannesburg Hospital and Milpark Hospital, Parktown, University of the Witwatersrand, Johannesburg, South Africa
2 Centre for Diabetes and Endocrinology, Houghton, University of the Witwatersrand, Johannesburg, South Africa
3 Lancet Laboratories, Richmond, Johannesburg, South Africa
Corresponding author: Patrick H Dessein, Dessein@lancet.co.za
Received: 9 Jan 2005 Revisions requested: 24 Jan 2005 Revisions received: 2 Feb 2005 Accepted: 15 Feb 2005 Published: 24 Mar 2005
Arthritis Research & Therapy 2005, 7:R634-R643 (DOI 10.1186/ar1717)
This article is online at: http://arthritis-research.com/content/7/3/R634
© 2005 Dessein et al.; licensee BioMed Central Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/
2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Cardiovascular event rates are markedly increased in
rheumatoid arthritis (RA), and RA atherogenesis remains poorly
understood The relative contributions of traditional and
nontraditional risk factors to cardiovascular disease in RA await
elucidation The present study comprises three components
First, we compared biomarkers of endothelial dysfunction
(vascular cell adhesion molecule [VCAM]-1, intercellular
adhesion molecule [ICAM]-1 and endothelial leucocyte
adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy
control individuals before and after controlling for traditional and
nontraditional cardiovascular risk factors, including
high-sensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor
necrosis factor-α Second, we investigated the potential role of
an extensive range of patient characteristics in endothelial
dysfunction in the 74 RA patients Finally, we assessed
associations between biomarkers of endothelial dysfunction and
ultrasonographically determined common carotid artery intima–
media thickness and plaque in RA The three biomarkers of
endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor
necrosis factor-α, were higher in patients than in control
individuals (P < 0.0001) Patients were also older, exercised
less and had a greater waist circumference, blood pressure and
triglyceride levels (P ≤ 0.04) Five patients had diabetes
Differences in endothelial function were no longer significant
between patients and controls (P = 0.08) only after both
traditional and nontraditional cardiovascular risk factors were controlled for In the 74 RA patients, IL-6 predicted levels of all
three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular
risk factors (P ≤ 0.02) VCAM-1 was associated with common
carotid artery intima–media thickness (P = 0.02) and plaque (P
= 0.04) in RA Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in
RA Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA
Introduction
Cardiovascular disease is an increasingly recognized
contrib-utor to excess morbidity and mortality in rheumatoid arthritis
(RA) [1-5] Traditional cardiovascular risk factors do not
ade-quately accunt for the extent of cardiovascular disease in RA
[3,5] Although hypertension and age are potential additional
contributors to cardiovascular events in this disease [6],
mark-ers of current and cumulative inflammation (white cell counts and radiographic joint damage, respectively) are associated with ultrasonographically determined subclinical atherosclero-sis [7,8] – a predictor of cardiovascular events [9]
Atherosclerosis often develops subclinically over prolonged periods of time; therefore, it may be too insensitive to show
CCA = common carotid artery; DMARD = disease-modifying antirheumatic drug; ELAM = endothelial leucocyte adhesion molecule; GFR = glomer-ular filtration rate; hs-CRP = high-sensitivity C-reactive protein; ICAM = intercellglomer-ular adhesion molecule; IL = interleukin; IMT = intima–media
thick-ness; RA = rheumatoid arthritis; TNF = tumour necrosis factor; VCAM = vascular cell adhesion molecule.
Trang 2associations with recently acquired or temporarily active
mod-ifiable cardiovascular risk factors, such as systemic
inflamma-tion secondary to recent onset or uncontrolled RA Clearly,
other outcome variables that can identify patients at risk for
cardiovascular disease at any point in time are needed in RA
One such potential marker is endothelial dysfunction – an
essential step in atherogenesis [10] Most if not all risk factors
that are related to cardiovascular disease are also associated
with endothelial dysfunction, and the process is reversible with
effective treatment of operative risk factors [10] Endothelial
status may be regarded as an integrated index of all
athero-genic and atheroprotective factors present in an individual
[10]
Several methods have been employed to assess endothelial
function Using ultrasonographically measured brachial artery
flow mediated dilatation or vasodilatory responses to
intrabra-chial artery infusion of acetylcholine, some [11-14] but not all
investigators [15] have shown impaired endothelial function in
RA Endothelial dysfunction was related to inflammation [12]
and HLA-DR1 [11], and was found to improve with infliximab
treatment [13] An alternative method to assess endothelial
function involves the measurement of biomarkers of
endothe-lial activation and dysfunction (circulating vascular cell
adhe-sion molecule [VCAM]-1, intercellular adheadhe-sion molecule
[ICAM]-1, and endothelial leucocyte adhesion molecule
[ELAM]-1 [or selectin]) [16-20] Elevated circulating adhesion
molecules are associated with cardiovascular risk factors [17]
and predict atherosclerosis and cardiovascular events
[18-20] The measurement of circulating adhesion molecules may
not add much predictive information to that provided by more
established risk factors in the general population [21] In
con-trast, it has been reported that such biomarkers play a more
important role than traditional risk factors in cardiovascular
dis-ease in RA [22,23] Important in this context is that high
circu-lating adhesion molecule levels may not only reflect synovial
inflammation but also indicate exposure of the systemic
vascu-lar endothelium to high circulating cytokine concentrations
[24]
To our knowledge, the relative impact of traditional versus
non-traditional cardiovascular risk factors on endothelial
dysfunc-tion as assessed using biomarkers has not been reported in
RA The present study comprises three components First, we
compared biomarkers of endothelial dysfunction in 74 RA
patients and 80 healthy control individuals before and after
controlling for potential explanatory variables, including both
traditional and nontraditional cardiovascular risk factors
Sec-ond, we investigated in the 74 RA patients the potential role
played by an extensive range of patient characteristics in
endothelial dysfunction Finally, we assessed the association
between biomarkers of endothelial dysfunction and
ultrasono-graphically determined common carotid artery (CCA) intima–
media thickness (IMT) and plaque [9]
Materials and methods
Biomarkers of endothelial dysfunction in RA patients and healthy control individuals
Seventy-six consecutive patients who fulfilled the American College of Rheumatology criteria for RA [25] were invited to participate Only two patients refused, and the remaining 74 were included Patients receiving lipid-lowering and antidia-betic medications were excluded The baseline clinical and routine laboratory characteristics of the included RA patients are reported elsewhere [26] Eighty-three individuals with no known diseases and who were not taking any medication agreed to act as controls These were friends, patient friends and laboratory staff Three of them were excluded because they were found to have impaired fasting glucose (plasma glu-cose >5.5 mmol/l); the remaining 80 were included in the study The study was approved by the Ethics Committees for Research on Human Subjects (Medical) of the University of the Witwatersrand and the Milpark Hospital
We recorded traditional cardiovascular risk factors in both RA patients and control individuals using previously reported methods (Table 1) [26] We also recorded the following non-traditional cardiovascular risk factors: circulating high-sensitiv-ity C-reactive protein (hs-CRP), cytokines (IL-1, IL-6 and tumor necrosis factor [TNF]-α), cytokine suppressant therapy (dis-ease-modifying antirheumatic drug [DMARD] and prednisone use) and biomarkers of endothelial dysfunction (Tables 1 and 2) Blood sampling was performed on the same day that clini-cal data were recorded Fasting blood samples were taken between 08:00 and 10:00 hours All laboratory analyses except for assessments of cytokines and biomarkers of endothelial dysfunction were performed within 2 hours of sam-pling These comprised lipids, hs-CRP and other laboratory tests that were performed for the second component of the study, which was conducted in the RA patients only (see below) Blood samples drawn for determination of cytokines and biomarkers of endothelial dysfunction were stored at -70°C before laboratory testing Cytokines and adhesion mole-cules were measured using enzyme-linked immunosorbent assays (Hiss Diagnostics GmbH, Freiburg, Switzerland) The intra-assay and inter-assay coefficients of variation (respec-tively) were 5.1% and 8.6% for IL-1, 3.4% and 5.2% for IL-6, 6.9% and 7.4% for TNF-α, 3.1% and 5.2% for VCAM-1, 4.1% and 7.7% for ICAM-1, and 5.4% and 6.0% for ELAM-1
Statistical analysis
The traditional and nontraditional risk factors were compared using the Mann–Whitney U-test (continuous variables) and the χ2 test (dichotomous variables; Table 1) Apart from hs-CRP, cytokines and cytokine suppressant therapy (DMARD and glucocorticoid use), several traditional cardiovascular risk factors differed between RA patients and control individuals The ability of traditional and nontraditional cardiovascular risk factors to account for differences in the levels of biomarkers of endothelial dysfunction between RA patients and control
Trang 3individuals was assessed in logistic regression models (Table
2), using RA status as the dependent variable (RA = 1,
non-RA control = 0) Continuous variables that were not normally
distributed were logarithmically transformed P < 0.05 was
considered statistically significant
Relationship between patient characteristics and
biomarkers of endothelial dysfunction in RA patients
For the second component of the study, recorded variables
other than cytokines and biomarkers of endothelial dysfunction
are summarized in Tables 3 and 4 A descriptive analysis of
these variables in the current cohort was previously reported
[26] Although 10 patients were on thyroxine replacement therapy and eight had subclinical hypothyroidism (thyrotropin
>4 µIU/ml and normal thyroxine levels) [27], none had clinical hypothyroidism (decreased thyroxine levels) at the time of the study IgM rheumatoid factor was determined using an immu-noturbidimetric test on the Olympus AU 600 analyzer The intra-assay and inter-assay coefficients of variation for rheuma-toid factor were 3.4% and 4.6%, respectively
Statistical analysis
Associations between patient characteristics and biomarkers
of endothelial dysfunction were first assessed by univariate
Table 1
Cardiovascular risk factors in RA patients and control individuals
Traditional risk factors
Nontraditional risk factors
Cytokine suppressant therapy
Results are expressed as median (range) unless indicated otherwise Data were analyzed using the Mann–Whitney U-test (continuous variables)
or the χ 2 test (dichotomous variables) DBP, diastolic blood pressure; DMARD, disease-modifying antirheumatic drug; HDL, high-density
lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IL, interleukin; RA, rheumatoid arthritis; SBP, systolic blood pressure; TNF, tumour
necrosis factor.
Trang 4analyses comprising the Spearman correlation coefficients
(continuous variables; Table 3) and the Mann–Whitney U-test
(dichotomous variables; Table 4) Because many univariate
analyses were conducted in this component of the study, P <
0.01 was considered statistically significant Because IL-6,
rheumatoid factor and low glomerular filtration rate (GFR)
were associated with biomarkers of endothelial dysfunction,
their potential roles as predictors of endothelial dysfunction
were further assessed after controlling for traditional
cardio-vascular risk factors in multivariable regression models (Table
5) Continuous variables that were not normally distributed
were logarithmically transformed In these multivariable
mod-els, P < 0.05 was considered statistically significant.
Associations between biomarkers of endothelial
dysfunction and common carotid artery intima–media
thickness and plaque in RA patients
The CCAs were evaluated using high resolution B-mode
ultra-sound Details of this investigation in the present cohort were
previously reported [26]
Statistical analysis
The associations between biomarkers of endothelial
dysfunc-tion and CCA IMT and plaque were determined using the
Spearman correlation coefficient and the Mann–Whitney U
test, respectively P < 0.05 was considered statistically
significant
Results
Biomarkers of endothelial dysfunction in RA patients
and healthy control individuals
The recorded baseline characteristics in the RA patients and
control individuals comprised traditional cardiovascular risk
factors, hs-CRP and cytokines (Table 1) RA patients were
younger, exercised less, had a higher waist circumference,
higher systolic and diastolic blood pressures, and higher
trig-lyceride levels than did control individuals Five RA patients
had diabetes that was being treated with dietary intervention
only With regard to nontraditional cardiovascular risk factors,
hs-CRP, IL-1, IL-6 and TNF-α concentrations were higher in
patients than in control individuals, and DMARD and pred-nisone were used by 56 and 11 RA patients, respectively No patient was being treated or had been treated with biological agents at the time of the study
Results for biomarkers of endothelial dysfunction in patients and control individuals are shown in Table 2 In univariate anal-ysis, all three biomarkers of endothelial dysfunction (VCAM-1, ICAM-1 and ECAM-1) were higher in patients than in control individuals These differences remained significant after con-trolling for cytokine suppressant agent (DMARD and pred-nisone) use (model 1) or traditional cardiovascular risk factors (model 2) After controlling for nontraditional cardiovascular risk factors, the differences in ELAM-1 between patients and control individuals were no longer significant (model 3) When traditional and nontraditional cardiovascular risk factors were simultaneously controlled for, the differences in levels of all three biomarkers of endothelial dysfunction were no longer significant between patients and control individuals (model 4)
Relationship between patient characteristics and biomarkers of endothelial dysfunction in RA patients
In univariate analysis, VCAM-1 was related to rheumatoid fac-tor titres and low GFR, ICAM-1 to rheumatoid facfac-tor titres and IL-6, and ELAM-1 to IL-6 (Table 4) None of the other recorded baseline characteristics in the 74 RA patients were associated with biomarkers of endothelial dysfunction (Tables 4 and 5)
After controlling for traditional cardiovascular risk factors in multivariable regression models, IL-6 was predictive of all three biomarkers of endothelial dysfunction, and rheumatoid factor titre and low GFR were both predictive of VCAM-1 and ICAM-1 (Table 5) Additional controlling for thyrotropin levels did not materially alter these models (data not shown)
Associations between biomarkers of endothelial dysfunction and common carotid artery intima–media thickness and plaque in RA patients
As previously reported, the median (range) CCA IMT was 0.654 mm (0.496–1.150 mm), and 23 (31%) patients had
Biomarkers of endothelial dysfunction in rheumatoid arthritis patients and control individuals
Model 1 a Model 2 b Model 3 c Model 4 d
VCAM-1 (pg/ml) 506 (253–1067) 747 (391–2077) <0.0001 <0.0001 <0.0001 <0.0001 0.08 ICAM-1 (pg/ml) 231 (82–857) 366 (135–993) <0.0001 0.0002 <0.0001 0.0005 0.08
Results are expressed as median (range) Unadjusted comparisons were done using the Mann–Whitney U-test and adjustments for potentially explanatory variables were made using logistic regression models a Adjusted for disease-modifying antirheumatic drug and prednisone use
b Adjusted for traditional risk factors (age; sex; race; smoking, alcohol and exercising status; diabetes; waist; systolic blood pressure; total cholesterol; high-density lipoprotein cholesterol; triglycerides) c Adjusted for nontraditional risk factors (high sensitivity C-reactive protein, interleukin IL-1, IL-6 and tumour necrosis factor- α ) d Adjusted for traditional and nontraditional risk factors ELAM, endothelial leukocyte adhesion molecule; ICAM, intercellular adhesion molecule; VCAM, vascular adhesion molecule.
Trang 5Table 3
Spearman correlations among biomarkers and potential cardiovascular risk factors
Demographic
Lifestyle
Systemic inflammation
Disease severity
Cytokines
Drug therapy
Current prednisone dose
(mg/day)
Cumulative prednisone dose
(mg)
Metabolic syndrome
Others
Trang 6plaque [26] Twenty-one (28%) patients had a CCA IMT under
0.600 mm and no plaque The role of clinical and routine
lab-oratory characteristics as predictors of common carotid
atherosclerosis in the present cohort was also previously
reported [26] VCAM-1 concentrations correlated with the
CCA IMT (rs = 0.280; P = 0.016) and were higher in patients
with plaque than in those without plaque (769 pg/ml [391–
2073 pg/ml] versus 703 pg/ml [445–2001 pg/ml]; P =
0.043) The associations between CCA findings and other
biomarkers did not achieve statistical significance
Discussion
Biomarkers of endothelial dysfunction in RA patients
and healthy control individuals
We found that biomarkers of endothelial dysfunction were
markedly higher in RA patients than in healthy control
individ-uals Increased circulating adhesion molecule concentrations
have been reported in RA [23,24,28,29] Our patients also
had higher hs-CRP and IL-1, IL-6 and TNF-α concentrations
than did control individuals, but these nontraditional
cardiovas-cular risk factors did not fully account for the differences in
biomarkers of endothelial dysfunction between patients and
control individuals Indeed, the RA patients also had generally
less favourable traditional cardiovascular risk factor profiles
than healthy control individuals
The younger age of the healthy control individuals included
reflects the difficulties in recruiting healthy aged persons who
are not taking any medication Hence, we controlled for age as
well as other traditional cardiovascular risk factors when
assessing the differences in biomarkers of endothelial
dys-function between patients and control individuals Of interest,
the body mass indices were similar in both groups, but
patients had higher waist circumference, blood pressure and
triglyceride levels The latter are features of the metabolic
syn-drome [5,30] Although differences in age and exercise habits
might have contributed to these findings, features of the met-abolic syndrome also cluster in RA because of inflammation-induced insulin resistance [5,30]
In multivariable models, traditional cardiovascular risk factors attenuated the differences in biomarkers of endothelial dys-function between patients and control individuals to a lesser extent than did nontraditional cardiovascular risk factors How-ever, the differences in endothelial function between patients and control individuals were no longer significant only after both traditional and nontraditional cardiovascular risk factors had been controlled for Our results also show the need for comprehensive assessment of cardiovascular risk factors in healthy individuals when comparing their endothelial function with that in RA patients
Relationship between patient characteristics and biomarkers of endothelial dysfunction in RA patients
We investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in RA IL-6, rheumatoid factor titre and low GFR predicted endothelial dys-function, as assessed using biomarkers
In multivariable analysis, IL-6 predicted endothelial dysfunction independent of traditional cardiovascular risk factors Chronic cytokine release from inflamed joints was previously implicated
in the increased production of adhesion molecules by endothelial cells in RA [4,31] Circulating cytokines could impair endothelial function directly [4] or through their effects
on insulin sensitivity and on CRP and fibrinogen (a major deter-minant of erythrocyte sedimentation rate [32]) production by the liver [4] In the present cohort of unselected RA patients, IL-6 was more strongly associated with endothelial dysfunc-tion than were CRP, erythrocyte sedimentadysfunc-tion rate and insulin resistance In contrast to IL-6, circulating IL-1 and TNF-α con-centrations were not associated with endothelial dysfunction
Polymorphonuclear cells
(×10 6 /l)
Urinary albumin/creatinine
(mg/mmol)
DBP, diastolic blood pressure; ELAM, endothelial leukocyte adhesion molecule; ESR, erythrocyte sedimentation rate; GFR, glomerular filtration rate; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; ICAM, intercellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; MP, methylprednisolone; QUICKI, Quantitative Insulin Sensitivity Check Index; SBP, systolic blood pressure; TNF, tumour
necrosis factor; VCAM, vascular adhesion molecule *P ≤ 0.01; **P < 0.006.
Spearman correlations among biomarkers and potential cardiovascular risk factors
Trang 7IL-1 and TNF-α are major proinflammatory cytokines in RA
joints and stimulate IL-6 production by synovial fibroblasts
[33-37], whereas IL-6 is a major circulating cytokine in RA that
induces the acute phase response, production of
immu-noglobulins by B cells and neuroendocrine alterations
[33,34,37,38] IL-6 promotes adhesion molecule expression
and stimulates macrophages to secrete monocyte
chemotac-tic protein-1 [39] Circulating IL-6 concentrations also predict
cardiovascular disease in the general population, independent
of hs-CRP levels [39]
Apart from IL-6, rheumatoid factor was also predictive of endothelial dysfunction independent of traditional cardiovas-cular risk factors in the present cohort The mechanism under-lying the strong association between rheumatoid factor and endothelial dysfunction in RA cannot be discerned from our
Table 4
Number of patients and biomarkers of endothelial dysfunction by sex, race, diabetes and medications used
Sex
Race
Diabetes
COX-2 inhibitor use
Traditional NSAID use
Aspirin use
Oestrogen use
DMARD use
Prednisone use
Antihypertensive agent use
Results for biomarkers are expressed as median (range) Data were analyzed using the Mann–Whitney U test No comparisons were significant at
P ≤ 0.01 COX-2, cyclooxygenase-2; DMARD, disease-modifying antirheumatic drug; ELAM, endothelial leukocyte adhesion molecule; ICAM,
intercellular adhesion molecule; NSAID, nonsteroidal anti-inflammatory drug; VCAM, vascular adhesion molecule.
Trang 8data However, rheumatoid factor may directly cause
endothe-lial injury [31] Direct evidence for a role for humoral immunity
in atherosclerosis was found by George and coworkers [40]
In their study repeated intraperitoneal administration of IgG
from serum of mice immunized with heat shock protein 65
enhanced fatty streak formation in mice in comparison with
their control anti-bovine serum albumin injected littermates
[40] Rheumatoid factor is produced by B cells that are highly
effective at presenting antigens to T cells [41] and T-cell
acti-vation in rheumatoid synovium is B-cell dependent [42] The
recently reported remarkable efficacy of B-cell depletion in
rheumatoid factor positive RA with rituximab [43] indicates
that B cells are key contributors to the immunopathogenesis
of RA In a recent autopsy report on two RA patients with
cor-onary artery disease the corcor-onary plaques and adventitia
con-tained large numbers of B cells, whereas in coronary artery
disease it is typical for lymphocytic infiltrates to consist almost
exclusively of T cells [44] These reports and our findings
sup-port a role for humoral mechanisms in RA atherogenesis
Finally, a low GFR also predicted endothelial dysfunction in
our RA patients Although only four (5%) patients had an
ele-vated serum creatinine (>115 µmol/l), GFR estimation using
the Cockcroft–Gault equation [45] revealed that 16 (22%)
patients had a GFR under 60 ml/min [26], which is indicative
of chronic kidney disease The high prevalence of
cardiovascular disease in individuals with chronic kidney
dis-ease has been amply reported [45] This is attributable to the
high prevalence of traditional risk factors such as older age,
high total cholesterol, low high-density lipoprotein cholesterol
and diabetes, as well as to nontraditional risk factors such as
oxidant stress, inflammation and, to a lesser extent,
hyperho-mocysteinaemia In the present cohort, varimax rotated factor
analysis confirmed strong relationships between low GFR,
age and hyperhomocysteinaemia [26] Also, independent of
age as well as other traditional cardiovascular risk factors, a
low GFR remained independently predictive of endothelial
dysfunction in our patients whereas hs-CRP was not
associ-ated with circulating adhesion molecules In support of an
important role of oxidant stress in cardiovascular disease
com-plicating chronic kidney disease, both vitamin E 800 U daily and acetylcysteine 600 mg twice daily were shown to decrease cardiovascular events in randomized controlled trials
in haemodialysis patients [45] Whether such interventions could decrease cardiovascular disease in RA may deserve fur-ther study
Associations between biomarkers of endothelial dysfunction and common carotid artery intima–media thickness and plaque in RA patients
In a previous study conducted by Wallberg-Jonsson and cow-orkes [23] in 39 RA patients, ICAM-1 and selectin concentra-tions were found to be related to ultrasonographically detected CCA and femoral artery plaque as well as to haemo-static factors of endothelial origin We found that VCAM-1 was associated with ultrasonographically determined CCA IMT and plaque Taken together, these data further support the contention that circulating adhesion molecules are linked to cardiovascular disease in RA
Study limitations
We assessed cardiovascular risk comprehensively and our results are in keeping with previously reported paradigms of cardiovascular disease in RA [4,5,31] However, our findings must be reproduced in a longitudinal study and investigations
of a larger cohort is likely to reveal more independent associa-tions between biomarkers of endothelial dysfunction and car-diovascular risk factors
Conclusion
We found that the biomarkers of endothelial dysfunction VCAM-1, ICAM-1 and ELAM-1 were higher in 74 RA patients than in 80 healthy control individuals In multivariable regres-sion models these differences could be accounted for by non-traditional cardiovascular risk factors (high hs-CRP, IL-1, IL-6 and TNF-α) and unfavourable traditional cardiovascular risk factor profiles in RA patients IL-6, rheumatoid factor titre and low GFR predicted endothelial dysfunction, as assessed by biomarkers, independent of traditional cardiovascular risk fac-tor in the 74 RA patients VCAM-1 was associated with CCA
Partial correlation coefficients between IL-6, rheumatoid factor and glomerular filtration rate, and biomarkers of endothelial dysfunction in rheumatoid arthritis patients
a The correlation coefficients shown are controlled for traditional risk factors (age; sex; race; smoking, alcohol and exercising status; diabetes; waist; systolic blood pressure; total cholesterol; high-density lipoprotein cholesterol; triglycerides) in multivariable regression models ELAM, endothelial leukocyte adhesion molecule; GFR, glomerular filtration rate; ICAM, intercellular adhesion molecule; IL, interleukin; VCAM, vascular adhesion molecule.
Trang 9atherosclerosis in RA Those DMARDs that are most effective
at suppressing both cytokine and rheumatoid factor
produc-tion may also be most effective in protecting against
cardio-vascular disease in RA In addition, interventions aimed at
preserving renal function may need to be considered in
cardi-ovascular disease prevention in RA
Competing interests
The author(s) declare that they have no competing interests
Authors' contributions
PD conceived the study, collected the data, performed the
sta-tistical analysis and drafted the manuscript BJ participated in
the study design, interpretation of the data and drafting the
manuscript SS conducted the immunoassays
Acknowledgements
The authors thank Dr Milton Tobias for reading the radiographs, and Ms
Belinda Stevens for carrying out the ultrasonographic carotid artery
eval-uations The study was supported in part by the South African
Circula-tory Disorders Research Fund.
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